Salt Forms Of 4-Cyano-N-(4,4-Dimethylcyclohex-1-EN-1-YL)-6-(2,2,6,6-Tetramethyltetrahydro-2H-Pyran-4-YL)Pyridin-3-YL)-1H-Imidazole-2-Carboximide

ABSTRACT

The present disclosure discusses salt forms of 4-cyano-N-[2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl]-1H-imidazole-2-carboxamide.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/737,273, filed on Jan. 8, 2020, which is a divisional of U.S. patentapplication Ser. No. 16/289,280, filed on Feb. 28, 2019 (now U.S. Pat.No. 10,562,892), which is a divisional of U.S. patent application Ser.No. 15/651,829, filed on Jul. 17, 2017 (now U.S. Pat. No. 10,266,522),which claims priority to U.S. Provisional Patent Application No.62/363,657, filed Jul. 18, 2016. The entirety of each of theseapplications is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

The present inventions are directed to salt forms of4-cyano-N-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)-1H-imidazole-2-carboxamide.

BACKGROUND

Protein kinases are enzymes that serve as key components of signaltransduction pathways by catalyzing the transfer of the terminalphosphate from adenosine 5′-triphosphate (ATP) to the hydroxy group oftyrosine, serine and threonine residues of proteins. As a consequence,protein kinase inhibitors and substrates are valuable tools forassessing the physiological consequences of protein kinase activation.The overexpression or inappropriate expression of normal or mutantprotein kinases in mammals has been demonstrated to play significantroles in the development of many diseases, including cancer anddiabetes.

Protein kinases can be divided into two classes: those whichpreferentially phosphorylate tyrosine residues (protein tyrosinekinases) and those which preferentially phosphorylate serine and/orthreonine residues (protein serine/threonine kinases). Protein tyrosinekinases perform diverse functions ranging from stimulation of cellgrowth and differentiation to arrest of cell proliferation. They can beclassified as either receptor protein tyrosine kinases or intracellularprotein tyrosine kinases. The receptor protein tyrosine kinases, whichpossess an extracellular ligand binding domain and an intracellularcatalytic domain with intrinsic tyrosine kinase activity, aredistributed among 20 subfamilies.

Feline McDonough Sarcoma (FMS) is the receptor-tyrosine kinaseresponsible for cellular response to colony stimulating factor-1(CSF-1). CSF-1 is the primary growth factor for themacrophage/osteoclast lineage. Inhibitors of FMS kinase reducemacrophage survival in tissues and osteoclastogenesis in bone.Accordingly, diabetes, angiogenesis, psoriasis, restenosis, oculardiseases, schizophrenia, rheumatoid arthritis, cardiovascular diseaseand cancer are exemplary of pathogenic conditions that have been linkedwith abnormal protein tyrosine kinase activity.

4-Cyano-N-[2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl]-1H-imidazole-2-carboxamideexhibits an inhibitory activity against FMS to treat diseases wheremacrophages and osteoclasts are pathogenic, namely rheumatoid arthritisand cancer metastasis to bone.

There remains a need to provide alternate forms of4-cyano-N-[2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl]-1H-imidazole-2-carboxamide.

SUMMARY

The present disclosure provides salt forms of4-cyano-N-[2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl]-1H-imidazole-2-carboxamide.Pharmaceutical compositions comprising these salt forms and methods ofusing these salt forms for inhibiting colony-stimulating factor-1receptor are also described.

BRIEF DESCRIPTION OF THE DRAWINGS

The summary, as well as the following detailed description, is furtherunderstood when read in conjunction with the appended drawings. For thepurpose of illustrating the invention, there are shown in the drawingsexemplary embodiments of the invention; however, the invention is notlimited to the specific methods, compositions, and devices disclosed. Inaddition, the drawings are not necessarily drawn to scale. In thedrawings:

FIG. 1 is an X-ray powder diffraction (XRPD) pattern for Compound A.

FIG. 2 is an XRPD pattern for the HCl salt of Compound A.

FIG. 3 is a differential scanning calorimetry (DSC) thermogram ofCompound A.

FIG. 4 is a DSC thermogram for the HCl salt of Compound A.

FIG. 5 is a thermogravimetric analysis (TGA) spectrum of Compound A.

FIG. 6 is a TGA spectrum of the HCl salt of Compound A.

FIG. 7 is a dynamic vapor sorption (DVS) spectrum of Compound A showingtwo cycles of adsorption/desorption.

FIG. 8 is the XRPD pattern of Compound A before (bottom) and after (top)DVS.

FIG. 9 is the DVS spectrum of the HCl salt of Compound A.

FIG. 10 is a solution proton nuclear magnetic resonance (¹H-NMR)spectrum of Compound A.

FIGS. 11-19 are solution ¹H-NMR spectra of Compound A (bottom spectra ofeach of FIGS. 11-19) and the sulfate salt, phosphate salt, mesylatesalt, tosylate salt, besylate salt, acetate solid residue, malonatesolid residue, citrate solid residue, and malate solid residue,respectively, of Compound A (top spectra of each Figure, respectively).The shaded inserts correlated to portions of each spectrum.

FIGS. 20-28 are XRPD patterns for the sulfate salt, phosphate salt,mesylate salt, tosylate salt, besylate salt, acetate solid residue,malonate solid residue, citrate solid residue, and malate solid residue,respectively, of Compound A.

FIGS. 29-37 are TGA thermograms (starting at top) and differentialscanning calorimetry (DSC) thermograms (starting at bottom) for thesulfate salt, phosphate salt, mesylate salt, tosylate salt, besylatesalt, acetate solid residue, malonate solid residue, citrate solidresidue, and malate solid residue, respectively, of Compound A.

FIG. 38 is a DVS spectrum of the phosphate salt of Compound A showingtwo cycles of adsorption.

FIG. 39 are XRPD patterns of the phosphate salt of Compound A before(top/upper spectrum) and after DVS (bottom/lower spectrum).

FIG. 40 is a DVS spectrum of the mesylate salt of Compound A showing twocycles of adsorption.

FIG. 41 are XRPD patterns of the mesylate salt of Compound A before(top/upper spectrum) and after DVS (bottom/lower spectrum).

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The disclosure may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. It is to be appreciated that certain features ofthe disclosed compositions and methods which are, for clarity, describedherein in the context of separate aspects, may also be provided incombination in a single aspect. Conversely, various features of thedisclosed compositions and methods that are, for brevity, described inthe context of a single aspect, may also be provided separately or inany subcombination.

The term “subject” includes humans. The terms “human,” “patient,” and“subject” are used interchangeably herein.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

Some of the quantitative expressions given herein are not qualified withthe term “about.” It is understood that whether the term “about” is usedexplicitly or not, every quantity given herein is meant to refer to theactual given value, and it is also meant to refer to the approximationto such given value that would reasonably be inferred based on theordinary skill in the art, including approximations due to theexperimental and/or measurement conditions for such given value.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the disclosure isadministered. A “pharmaceutically acceptable excipient” refers to asubstance that is non-toxic, biologically tolerable, and otherwisebiologically suitable for administration to a subject, such as an inertsubstance, added to a pharmacological composition or otherwise used as avehicle, carrier, or diluent to facilitate administration of an agentand that is compatible therewith. Examples of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

Further, some of the quantitative expressions herein are recited as arange from about amount X to about amount Y. It is understood thatwherein a range is recited, the range is not limited to the recitedupper and lower bounds, but rather includes the full range from aboutamount X through about amount Y, or any amount or range therein.

Described herein are novel salt forms of4-cyano-N-[2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl]-1H-imidazole-2-carboxamide,which has the following structure and is identified herein as “CompoundA.” In some embodiments, Compound A is a free base.

In the development of pharmaceuticals, in particular, orally delivereddrugs, it is often advantageous to have novel salt forms of such drugsthat possess improved physical properties, for example, increasedaqueous solubility and stability. The salt forms of Compound A describedherein possess improved properties over those solid forms of Compound Apreviously described. In some embodiments, the salt forms have improvedmoisture uptake as compared to Compound A.

Compound A (as a free base) and its hydrochloride salt may be prepared,for example, as described in U.S. Pat. No. 8,497,376 and US PatentPublication No. 2014/0045789, which are incorporated herein byreference, as well as using the procedures described in Example 1. Insome embodiments, Compound A is prepared from its hydrochloride salt. Inother embodiments, Compound A is prepared from its hydrochloride salt asdescribed in Example 1.

Various salt forms of Compound A are described and characterized herein.The salt forms of Compound A described herein include a sulfate salt,phosphate salt, mesylate salt, tosylate salt and besylate salt. Thesolid residues isolated from screening experiments using acetic acid(acetate), citric acid (citrate), malonic acid (malonate) and malic acid(malate) exhibit characteristic that suggest a form other than that ofthe starting material (Compound A freebase) was prepared, although theexact nature and identity of these residues was not fully determined.

In some embodiments, a sulfate salt of Compound A is provided. In oneaspect, the sulfate form of Compound A is amorphous. The sulfate salt ofCompound A produces a DSC thermogram comprising endothermic events withpeak temperatures at about 47.4° C., about 207.2° C., and about 232.8°C. The sulfate salt of Compound A may further be characterized by a DSCthermogram of FIG. 29. The sulfate salt of Compound A may further becharacterized by an ¹H-NMR spectrum substantially as depicted in FIG.11. The amorphous form of the sulfate salt of Compound A may becharacterized by an XRPD pattern substantially as depicted in FIG. 20.

In other embodiments, a phosphate salt of Compound A is provided. In oneaspect, the phosphate form of Compound A is crystalline. In a preferredaspect, a crystalline form of a phosphate salt of Compound A produces anX-ray powder diffraction pattern comprising peaks at 6.3, 6.7, and 20.0degrees two theta±0.2 degrees two theta. The XRPD pattern of acrystalline phosphate salt of Compound A may further comprise one ormore of the following peaks: 13.3, 17.0, 17.7, 18.2, or 18.8 degrees twotheta±0.2 degrees two theta. A crystalline phosphate salt of Compound Afurther may be characterized by an XRPD substantially as depicted inFIG. 21. The phosphate salt of Compound A may also be characterized by aDSC thermogram comprising endothermic events with peak temperatures atabout 192.3° C. and about 222.2° C. The phosphate salt of Compound A mayfurther be characterized by a DSC thermogram substantially as depictedin FIG. 30. The phosphate salt may also be characterized by a ¹H-NMRspectrum substantially as depicted in FIG. 12. The phosphate saltadditionally may be characterized by a DVS substantially as depicted inFIG. 38. The phosphate salt of Compound A may further be characterizedby an X-ray powder diffraction pattern comprising those peaks identifiedin Table 1, wherein the relative intensity of the peaks is greater thanabout 2%, more preferably greater than about 5%, more preferably greaterthan about 10%.

In further embodiments, a mesylate salt of Compound A is provided. Insome aspects, the mesylate salt of Compound A is crystalline. Acrystalline form of a mesylate salt of Compound A may produce an XRPDpattern comprising peaks at 6.0, 8.1 and 18.1 degrees two theta±0.2degrees two theta. A crystalline form of a mesylate salt of Compound Amay produce an XRPD pattern further comprising one or more of thefollowing peaks: 5.0, 6.3, 18.9, or 24.3 degrees two theta±0.2 degreestwo theta. A crystalline mesylate salt of Compound A may also becharacterized by an XRPD pattern substantially as depicted in FIG. 22.The mesylate salt may further be characterized by a DSC thermogramcomprising an endotherm with a peak temperature at about 256.3° C. Themesylate salt may also be characterized by a DSC thermogramsubstantially as depicted in FIG. 31. The mesylate salt may further becharacterized by a solution ¹H-NMR spectrum of FIG. 13. The mesylatesalt of Compound A may further be characterized by an X-ray powderdiffraction pattern comprising those peaks identified in Table 2,wherein the relative intensity of the peaks is greater than about 2%,preferably greater than about 5%, more preferably greater than about10%, more preferably greater than about 25%.

In some aspects, the tosylate salt form of Compound A is crystalline. Acrystalline tosylate salt of Compound A may produce an XRPD patterncomprising peaks at 5.1, 6.4 and 6.5 degrees two theta±0.2 degrees twotheta. A crystalline tosylate salt of Compound A may produce an XRPDpattern that further comprises one or more of the following peaks: 5.8,5.9, 16.3, 17.2, or 19.6 degrees two theta±0.2 degrees two theta. Acrystalline tosylate salt of Compound A may also be characterized by anXRPD pattern substantially as depicted in FIG. 23. The tosylate salt mayfurther characterized by a DSC thermogram comprising endothermic eventswith peak temperatures at about 155.9° C., about 207.4° C. and about255.9° C. The tosylate salt may also be characterized by a DSCthermogram substantially as depicted in FIG. 32. The tosylate salt mayfurther be characterized by a solution ¹H-NMR spectrum of FIG. 14. Thetosylate salt of Compound A may further be characterized by an X-raypowder diffraction pattern comprising those peaks identified in Table 3,wherein the relative intensity of the peaks is greater than about 2%,more preferably greater than about 5%, preferably greater than about10%, more preferably greater than about 25%, more preferably greaterthan about 50%.

In still further embodiments, a besylate salt of Compound A is provided.In some aspects, the besylate salt of Compound A is crystalline. In someaspects, a crystalline form of a besylate salt of Compound A may producean XRPD pattern comprising peaks at 5.8, 6.3, 17.1, 17.4, and 17.6degrees two theta±0.2 degrees two theta. The XRPD pattern of acrystalline besylate salt may further comprise one or more of thefollowing peaks: 7.8, 8.6, 8.9, 18.2, 18.9, 19.6 or 23.0 degrees twotheta±0.2 degrees two theta. A crystalline besylate salt of Compound Amay be further characterized by an XRPD pattern substantially asdepicted in FIG. 24. The besylate salt of Compound A may also becharacterized by a DSC thermogram comprising endothermic events withpeak temperatures at about 51.5° C., about 164.8° C., and about 212.2°C. The besylate salt of Compound A may be further characterized by a DSCspectrum substantially as depicted in FIG. 33. The besylate salt ofCompound A may also be characterized by a solution ¹H-NMR spectrum ofFIG. 15. The besylate salt of Compound A may further be characterized byan X-ray powder diffraction pattern comprising those peaks identified inTable 4, wherein the relative intensity of the peaks is greater thanabout 2%, preferably greater than about 5%, more preferably greater thanabout 10%, more preferably greater than about 25%.

In some aspects, an acetate solid residue of Compound A is provided. Theacetate solid residue (i.e. the solid residue isolated from thescreening experiment with acetic acid) showed a pattern similar toCompound A, as shown in FIG. 25. In some aspects, the acetate solidresidue of Compound A is crystalline. A crystalline acetate solidresidue of Compound A may produce an XRPD pattern having at least threepeaks at 6.1, 6.3, 9.2, 12.7, 15.1, and 18.4 degrees two theta±0.2degrees two theta. The XRPD pattern of a crystalline acetate salt ofCompound A may further comprise one or more of the following peaks: 9.4or 14.6 degrees two theta±0.2 degrees two theta. A crystalline acetatesalt of Compound A may also be characterized by an XRPD patternsubstantially as depicted in FIG. 25. A DSC thermogram of the acetateexperiment solid residue exhibited an endothermic event with a peaktemperature at about 210.9° C., as shown in FIG. 34. The acetate solidresidue exhibited a solution ¹H-NMR spectrum as shown in FIG. 16. Theacetate solid residue of Compound A may further be characterized by anX-ray powder diffraction pattern comprising those peaks identified inTable 5, wherein the relative intensity of the peaks is greater thanabout 2%, preferably greater than about 5%, more preferably greater thanabout 10%.

In some aspects, a malonate solid residue of Compound A is provided. Themalonate solid residue (i.e. the solid residue isolated from thescreening experiment with malonic acid) showed a pattern similar toCompound A, as shown in FIG. 26. In some aspects, the malonate solidresidue of Compound A is crystalline. A crystalline malonate solidresidue of Compound A may be characterized by an XRPD pattern comprisingpeaks at 6.3, 6.9, and 17.0 degrees two theta±0.2 degrees two theta. TheXRPD pattern of a crystalline malonate salt of Compound A may alsocomprise one or more of the following peaks: 7.4, 12.5, 18.8 or 23.0degrees two theta±0.2 degrees two theta. A crystalline malonate solidresidue of Compound A may also be characterized by an XRPD patternsubstantially as depicted in FIG. 26. The DSC thermogram of the malonatesolid residue exhibited endothermic events with peak temperatures atabout 174.6°, about 210.3° C., and about 220.7° C., as shown in FIG. 35.The malonate solid residue exhibited a solution ¹H-NMR spectrum as shownin FIG. 17. The malonate solid residue of Compound A may further becharacterized by an X-ray powder diffraction pattern comprising thosepeaks identified in Table 6, wherein the relative intensity of the peaksis greater than about 2%, preferably greater than about 5%, morepreferably greater than about 10%.

In some aspects, a citrate solid residue of Compound A is provided. Thecitrate solid residue (i.e. the solid residue isolated from thescreening experiment with citric acid) showed a pattern similar toCompound A, as shown in FIG. 27. In some aspects, the citrate solidresidue of Compound A is in a crystalline form. A crystalline citratesolid residue of Compound A may be characterized by an XRPD patterncomprising peaks at 6.3, 17.0 and 18.8 degrees two theta±0.2 degrees twotheta. The XRPD pattern of a crystalline citrate salt of Compound A mayfurther comprise one or more of the following peaks: 12.5, 14.0 or 23.0degrees two theta±0.2 degrees two theta. A crystalline citrate salt ofCompound A may also be characterized by an XRPD pattern substantially asdepicted in FIG. 27. A DSC thermogram of the citrate solid residueexhibited endothermic events with peak temperatures at about 134.3° C.,about 212.6° C., and about 221.5° C., as shown in FIG. 36. The citratesolid residue exhibited a solution ¹H-NMR spectrum as shown in FIG. 18.The citrate solid residue of Compound A may further be characterized byan X-ray powder diffraction pattern comprising those peaks identified inTable 7, wherein the relative intensity of the peaks is greater thanabout 2%, more preferably greater than about 5%, more preferably greaterthan about 10%.

In some aspects, a malate solid residue of Compound A is provided. Themalate solid residue (i.e. the solid residue isolated from the screeningexperiment with malic acid) showed a pattern similar to Compound A, asshown in FIG. 28. In yet further embodiments, a malate salt of CompoundA is provided. In some aspects, the malate salt of Compound A is in acrystalline form. A crystalline malate solid residue of Compound A maybe characterized by an XRPD pattern comprising peaks at 6.3, 12.6, 17.0,and 18.8 degrees two theta±0.2 degrees two theta. The XRPD of acrystalline malate salt of Compound A may further comprise one or moreof the following peaks: 14.0, 23.0, or 25.2 degrees two theta±0.2degrees two theta. A crystalline malate salt of Compound A may furtherbe characterized by an XRPD pattern substantially as depicted in FIG.28. The DSC thermogram of the malate solid residue exhibited anendothermic event with a peak temperature at about 195° C. as depictedin FIG. 37. The malate solid residue a solution ¹H-NMR spectrum as shownin FIG. 19. The malate solid residue of Compound A may further becharacterized by an X-ray powder diffraction pattern comprising thosepeaks identified in Table 8, wherein the relative intensity of the peaksis greater than about 2%, more preferably greater than about 5%, morepreferably greater than about 10%.

In treatment methods according to the disclosure, an effective amount ofa compound according to the disclosure is administered to a subjectsuffering from or diagnosed as having such a disease, disorder, orcondition. An “effective amount” means an amount or dose sufficient togenerally bring about the desired therapeutic benefit in patients inneed of such treatment for the designated disease, disorder, orcondition. Effective amounts or doses of the compounds of the presentdisclosure may be ascertained by routine methods such as modeling, doseescalation studies or clinical trials, and by taking into considerationroutine factors, e.g., the mode or route of administration or drugdelivery, the pharmacokinetics of the compound, the severity and courseof the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician. An example of a dose is in therange of from about 0.001 to about 200 mg of compound per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g.,BID, TID, QID). For a 70-kg human, an illustrative range for a suitabledosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about2.5 g/day.

In addition, the compounds may be used in combination with additionalactive ingredients in the treatment of the above conditions. Theadditional active ingredients may be coadministered separately with acompound of the disclosure or included in a pharmaceutical compositionaccording to the disclosure. The combination may serve to increaseefficacy (e.g., by including in the combination a compound potentiatingthe potency or effectiveness of a compound), decrease one or more sideeffects, or decrease the required dose of the compound.

The compounds are used, alone or in combination with one or moreadditional active ingredients, to formulate pharmaceutical compositionsof the disclosure. A pharmaceutical composition of the disclosurecomprises: (a) an effective amount of at least one compound inaccordance with the disclosure; and (b) a pharmaceutically acceptableexcipient.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of compounds may be prepared using suitable pharmaceuticalexcipients and compounding techniques known or that become available tothose skilled in the art. The compositions may be administered in theinventive methods by a suitable route of delivery, e.g., oral,parenteral, rectal, topical, or ocular routes, or by inhalation. Theroute of delivery includes immediate release, timed release andsustained release.

The preparation may be in the form of tablets, caplets, gelcaps,capsules, drops, sachets, dragees, powders, granules, lozenges, powdersfor reconstitution, liquid preparations, or suppositories. In someembodiments, the compositions are formulated for intravenous infusion,topical administration, or oral administration.

For oral administration, the compounds of the disclosure can be providedin the form of tablets or capsules, or as a solution, elixir, emulsion,or suspension. The total daily dosage of about 5 mg to 5 g daily,preferably about 10 mg to about 1000 mg daily, more preferably about 50mg to about 500 mg daily, may be accomplished by dosing once, twice,three, or four times per day.

Oral tablets may include one or more of a compound according to thedisclosure mixed with pharmaceutically acceptable excipients such asinert diluents, disintegrating agents, binding agents, lubricatingagents, sweetening agents, flavoring agents, coloring agents, suspendingagents, dyes and preservative agents. Suitable inert fillers includesodium and calcium carbonate, sodium and calcium phosphate, lactose,starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol,sorbitol, and the like. Liquid oral excipients may include ethanol,glycerol, water, and the like. Starch, polyvinyl-pyrrolidone, sodiumstarch glycolate, microcrystalline cellulose, and alginic acid aresuitable disintegrating agents. Binding agents may include starch andgelatin. The lubricating agent, if present, may be magnesium stearate,stearic acid or talc. If desired, the tablets may be coated with amaterial such as glyceryl monostearate or glyceryl distearate to delayabsorption in the gastrointestinal tract, or may be coated with anenteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the disclosure may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the disclosure with water, anoil such as peanut oil or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally containpharmaceutically acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The compounds may also be administered by non-oral routes. For example,the compositions may be formulated for rectal administration as asuppository. For parenteral use, including intravenous, intramuscular,intraperitoneal, or subcutaneous routes, the compounds of the disclosuremay be provided in sterile aqueous solutions or suspensions, buffered toan appropriate pH and isotonicity or in parenterally acceptable oil.Suitable aqueous vehicles include Ringer's solution and isotonic sodiumchloride. Such forms will be presented in unit-dose form such asampules, autoinjectors, or disposable injection devices, in multi-doseforms such as vials from which the appropriate dose may be withdrawn, orin a solid form or pre-concentrate that can be used to prepare aninjectable formulation. Illustrative infusion doses may range from about1 to 1000 μg/kg/minute of compound, admixed with a pharmaceuticalcarrier over a period ranging from several minutes to several days.Other routes of administration include, without limitation,intracerebral, intraventricular, intracerebroventricular, intrathecal,intracisternal, intraspinal and/or peri-spinal routes.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of thedisclosure may utilize a patch formulation to affect transdermaldelivery.

Compounds of the disclosure may alternatively be administered in methodsof this disclosure by inhalation, via the nasal or oral routes, e.g., ina spray formulation also containing a suitable carrier such as anaerosol or liquid spray.

The sulfate salt, phosphate salt, mesylate salt, tosylate salt andbesylate salt of Compound A alone, in combination with each other, or incombination with Compound A are accordingly useful in inhibitingcolony-stimulating factor-1 receptor. In some embodiments, the sulfatesalt, phosphate salt, mesylate salt, tosylate salt and besylate salt ofCompound A are useful in methods of treating a disease that is at leastone of osteoporosis, Paget's disease, rheumatoid arthritis and otherforms of inflammatory arthritis, osteoarthritis, prosthesis failure,osteolytic sarcoma, myeloma, or tumor metastasis to bone. In someembodiments, the disease is rheumatoid arthritis or cancer such ascancer metastasis to bone. In other embodiments, the sulfate salt,phosphate salt, mesylate salt, tosylate salt and besylate salt ofCompound A are useful in treating a disease that is glomerulonephritis,inflammatory bowel disease, sarcoidosis, congestive obstructivepulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis,HIV infection, psoriasis, diabetes, tumor-related angiogenesis,age-related macular degeneration, diabetic retinopathy, restenosis,schizophrenia, or Alzheimer's dementia. In further embodiments, thesulfate salt, phosphate salt, mesylate salt, tosylate salt and besylatesalt of Compound A is useful in treating pain, including skeletal paincaused by tumor metastasis or osteoarthritis, or visceral, inflammatory,or neurogenic pain. In still other embodiments, the sulfate salt,phosphate salt, mesylate salt, tosylate salt and besylate salt ofCompound A is useful in treating a disease that is ovarian cancer,uterine cancer, breast cancer, prostate cancer, lung cancer, coloncancer, stomach cancer, or hairy cell leukemia. In yet furtherembodiments, the sulfate salt, phosphate salt, mesylate salt, tosylatesalt and besylate salt of Compound A is useful in treating or preventingmetastasis from ovarian cancer, uterine cancer, breast cancer, prostatecancer, lung cancer, colon cancer, stomach cancer, or hairy cellleukemia. In other embodiments, the sulfate salt, phosphate salt,mesylate salt, tosylate salt and, besylate salt of Compound A is usefulin treating an autoimmune disease that is at least one of systemic lupuserythematosus, rheumatoid arthritis and other forms of inflammatoryarthritis, psoriasis, Sjogren's syndrome, multiple sclerosis, oruveitis.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

EXAMPLES Example 1: Synthesis of Compound A

The hydrochloride salt of Compound A was prepared as described in U.S.Pat. No. 8,497,376. Water (150 mL) was added to the hydrochloride saltof Compound A (about 10 g). The formed solution was stirred using a stirplate. After several days, the solution was filtered using a Buchnerglass filter under vacuum until the majority of the water was removed. Aflow of N₂ gas was then applied onto the surface of the precipitate forabout 1 hour to ensure complete removal of the solvent. The glass filterwas weighed before and after the filtration and the net weight wasrecorded.

A portion of the precipitate was analyzed using XRD and the resultsconfirmed the conversion of the salt to the free base, Compound A. Theglass filter was placed in a vacuum oven at 60° C. overnight to ensurecomplete dryness until a constant weight was obtained. Final examinationof the solids by XRD (e.g., FIG. 1), by comparison of the XRD of theisolated solids with the XRD of a sample of the HCl salt of Compound A(e.g., FIG. 2), confirmed the formation of the free base, Compound A.DSC (e.g., FIGS. 3 and 4) and TGA (e.g., FIGS. 5 and 6) analysis ofCompound A and the HCl salt provided further evidence of the formationof Compound A from the HCl salt.

Example 2: Synthesis of Compound A Salts

The salts and solid residues of Compound A were prepared using ninedifferent acidic counter-ions, (wherein the acidic counter-ion isprovided by the corresponding acid i.e., sulfuric, phosphoric,methanesulfonic, p-toluenesulfonic, benzenesulfonic, malonic, citric,1-malic, and acetic acids), using the following synthetic procedure.

Nine samples of Compound A (about 20 mg) prepared as described inExample 1 were added to nine separate 4 mL vials. About 1.1 molarequivalents of the acid (i.e., sulfuric acid, phosphoric acid,methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid,malonic acid, citric acid, 1-malic acid, and acetic acid) solutions (0.1M in acetone, freshly prepared) was independently added to each vial.The vials were stirred at 500 rpm and heat was applied as necessary. Allsolutions formed suspensions upon addition of the acid solution toCompound A, with the exception that the acetic acid solution remained aclear mixture. The suspensions were then heated to 40° C. with stirringfor about 30 minutes, but no additional clear solutions were observed.Since the solubility of Compound A in acetone is about 130 mg/mL, theformation of a suspension was interpreted as an indication that a saltor other non-free base material (e.g. solvate, co-crystal, etc.) hadformed.

All solutions were allowed to slowly crystallize by keeping the vialscapped for 24 hours, and then uncapping the vials and allowingevaporation to total dryness. All residual solids were then analyzedusing solution ¹H-NMR, XRPD, DSC and TGA as described below.

Example 3: XRPD Analysis

X-ray powder diffraction (XRPD) was performed using an X-raydiffractometer (Philips Model X'Pert PRO PW3040) equipped withX'Celerator detector and graded multilayer parabolic X-ray mirror. Thesample was scanned from 3 to 40° two theta at a step size of 0.0165° twotheta and a time per step of 48.260 seconds. The x-ray tube voltage andcurrent settings were 45 KV and 40 mA, respectively. The sample waspacked on a zero background holder and scanned under ambient conditionsof temperature and humidity. One skilled in the art will recognize thatdiffraction patterns and peak positions are typically independent of thediffractometer used and whether a specific calibration method wasutilized. Typically, the peak positions may vary by about ±0.2° twotheta, or less. The intensities (and relative intensities) of eachspecific diffraction peak may also vary as a function of variousfactors, including but not limited to particle size, orientation, samplepurity, etc. However the skilled person will be able to differentiatebetween the prepared forms including the sulfate salt, phosphate salt,mesylate salt, tosylate salt, besylate salt, acetate solid residue,malonate solid residue, citrate solid residue and malate solid residueof Compound A.

XRPD patterns of Compound A (prepared as described in Example 1 above)and the HCl salt of Compound A were obtained (see, FIGS. 1 and 2). Smallportions of each of the different suspensions from Example 1 werewithdrawn, prior to total evaporation, and placed to dry on a zerobackground X-ray sample holder for analysis. XRPD analyses of theresidues isolated from aliquots withdrawn from the suspensions showeddiffraction patterns which indicated that a form other than the CompoundA freebase was formed, indicating possible salt formation.

XRPD patterns of the solid residues isolated from the phosphate,mesylate, tosylate, and besylate solutions showed crystalline patternsthat were different than Compound A, indicating salt formations. TheXRPD pattern of the solid residue isolated from the sulfate solution wasfeatureless indicating an amorphous solid (see, FIG. 20).

Table 1 provides the peak listings for the XRPD of the phosphate salt(see, also, FIG. 21).

TABLE 1 Position [°2θ] Relative Intensity [%] 6.3 25.4 6.7 100.0 17.02.3 17.7 2.1 20.0 6.3

Table 2 provides the peak listings for the XRPD of the mesylate salt(see, also, FIG. 22).

TABLE 2 Position [°2θ] Relative Intensity [%] 5.0 9.5 6.0 100.0 6.3 6.98.1 43.2 12.1 3.3 13.5 2.2 16.3 2.7 17.6 2.8 18.1 31.1 18.9 4.8 19.7 3.420.8 2.3 24.3 9.5 24.7 2.2

Table 3 provides the peak listings for the XRPD of the tosylate salt(see, also, FIG. 23).

TABLE 3 Position [°2θ] Relative Intensity [%] 5.1 100.0 5.8 27.7 5.924.5 6.4 71.6 6.5 56.8 11.9 5.6 14.9 4.9 15.4 8.1 16.3 11.3 17.2 15.218.5 7.4 19.6 10.2 22.5 4.1 25.0 6.5 27.0 3.8 29.9 2.0

Table 4 provides the peak listings for the XRPD of the besylate salt(see, also, FIG. 24).

TABLE 4 Position [°2θ] Relative Intensity [%] 5.8 86.0 6.3 100.0 7.4 4.27.8 16.9 8.6 17.6 8.9 18.8 11.6 8.7 12.4 3.2 12.6 6.3 12.7 4.1 14.1 5.114.4 2.9 14.7 5.0 15.0 2.1 15.5 8.6 16.1 2.6 17.1 21.0 17.4 33.4 17.620.9 18.2 14.5 18.9 10.3 19.2 3.4 19.6 12.0 20.2 3.0 21.9 5.0 22.4 2.323.0 10.7 23.9 7.6 24.6 2.8 25.0 3.6 25.3 4.2

Table 5 provides the peak listings for the XRPD of the acetate solidresidue (see, also, FIG. 25).

TABLE 5 Position [°2θ] Relative Intensity [%] 6.1 100.0 6.3 17.3 9.235.1 9.4 6.1 12.7 18.6 14.6 4.9 15.1 31.8 18.4 19.9 21.1 4.0 22.2 2.324.8 2.1 26.3 3.7

Table 6 provides the peak listings for the XRPD of the malonate solidresidue (see, also, FIG. 26).

TABLE 6 Position [°2θ] Relative Intensity [%] 6.3 100.0 6.9 17.9 7.4 6.010.7 3.0 11.5 2.7 12.2 2.2 12.5 5.8 14.0 3.0 14.8 4.4 15.5 4.0 17.0 9.617.3 4.2 18.3 4.1 18.6 3.6 18.8 5.1 20.0 2.3 20.2 2.3 23.0 5.0 23.6 3.125.2 2.0

Table 7 provides the peak listings for the XRPD of the citrate solidresidue (see, also, FIG. 27).

TABLE 7 Position [°2θ] Relative Intensity [%] 6.3 100.0 12.5 4.5 14.03.5 17.0 5.1 18.8 5.8 23.0 2.6

Table 8 provides the peak listings for the XRPD of the malate solidresidue (see, also, FIG. 28).

TABLE 8 Position [°2θ] Relative Intensity [%] 6.3 100.0 12.6 5.6 14.04.1 17.0 7.5 18.8 8.7 23.0 5.0 25.2 2.9

Example 4: Solution ¹H-NMR Analysis

Solution ¹H-NMR analysis of Compound A was conducted and used as areference (see, FIG. 10). Solution ¹H-NMR patterns were then obtainedfrom the residues obtained in Example 1 (see, FIG. 11 (sulfate salt),FIG. 12 (phosphate salt), FIG. 13 (mesylate salt), FIG. 14 (tosylatesalt), FIG. 15 (besylate salt), FIG. 16 (acetate solid residue), FIG. 17(malonate solid residue), FIG. 18 (citrate solid residue), and FIG. 19(malate solid residue). The residues from the salt solutions showedchemical shifts of the protons at one or both of the 7.2 and 8.2 ppmpeaks attributable to the hydrogen atoms in the pyridine ring portion ofCompound A, indicating the possible formation of salts of Compound A.

Example 5: Thermal Analysis

Thermal analyses were performed using a TA instrument Model Q1000 DSC.The sample was run in an open aluminum pan. The reference used was anempty aluminum pan. The sample was scanned from 25° to 300° C. with aprogrammed heating rate of 10° C./min. Total weight loss of the samplewas obtained using a TA instrument Model Q5000 TGA. The sample wasplaced in a tarred aluminum pan, automatically weighed, and insertedinto the TGA furnace. The sample was scanned from 25° to 300° C. at aheating rate of 10° C./min with a 25 mL/min nitrogen sample purge and a10 mL/min nitrogen balance purge.

Differential scanning calorimetry and thermogravimetric analyses wereconducted on Compound A prepared as described in Example 1 above (see,FIGS. 3 and 5), the HCl salt of Compound A (see, FIGS. 4 and 6) and theresidues obtained in Example 2 (see, FIGS. 29-37).

The DSC thermogram of the sulfate salt (see FIG. 29) showed threeendothermic events with peak temperatures at 47.4° C. (61.0 J/g heat offusion), 207.2° C. (8.93 J/g heat of fusion), and 232.8° C. (2.06 J/gheat of fusion), respectively. TGA of the sulfate salt showed a two-stepweight loss of 2.3% between room temperature and 109° C. due to possibledehydration/desolvation, and 7.9% between 109° C. and 243° C. due tomelting/decomposition.

DSC analysis of the phosphate salt (see FIG. 30) showed two endothermicevents with peak temperatures at 192.3° C. (4.7 J/g heat of fusion), and222.2° C. (55.7 J/g heat of fusion), respectively. TGA of the phosphatesalt showed a two-step eight loss of 1.7% between room temperature and203° C. due to possible dehydration/desolvation, and 1.7% between 203°and 240° C. due to melting/decomposition.

DSC of the mesylate salt (see FIG. 31) showed one endothermic event dueto melting with a peak temperature at 256.3° C. (205.2 J/g heat offusion). TGA of the mesylate salt showed a two-step weight loss of 1.1%between room temperature and 222° C. due to possibledehydration/desolvation, and 5.7% between 222° C. and 264° C. due tomelting/decomposition.

DSC of the tosylate salt (see FIG. 32) showed two endothermic eventswith peak temperatures at 155.9° C. (2.2 J/g heat of fusion), 207.4° C.(31.5 J/g heat of fusion) and 255.9° C. (2.9 J/g heat of fusion),respectively. TGA of the tosylate salt showed a two-step weight loss of2.7% between room temperature and 168° C. due to possibledehydration/desolvation, and 3.4% between 168° C. and 244° C. due tomelting/decomposition.

DSC of the besylate salt (see FIG. 33) showed three endothermic eventswith peak temperatures at 51.5° C. (39.1 J/g heat of fusion), 164.8° C.(11.1 J/g heat of fusion), and 212.2° C. (21.0 J/g heat of fusion),respectively. TGA of the besylate salt showed a three-step weight lossof 1.7% between room temperature and 76° C. due to possibledehydration/desolvation, 0.6% between 76° C. and 183° C., and 3.5%between 183° C. and 256° C. due to melting/decomposition.

DSC of the acetate solid residue (see FIG. 34) showed one endothermicevent due to melting with a peak temperature at 210.9° C. (45.8 J/g heatof fusion). TGA of the acetate solid residue showed a two-step weightloss of 0.3% between room temperature and 157° C. due to possibledehydration/desolvation, and 3.9% between 157° C. and 232° C. due tomelting/decomposition.

DSC of the malonate solid residue (see FIG. 35) showed three endothermicevents with peak temperatures at 174.6° C. (117.4 J/g heat of fusion),210.3° C. (6.8 J/g heat of fusion), and 220.7° C. (37.2 J/g heat offusion), respectively. TGA of the malonate solid residue showed aone-step weight loss of 16.8% between 128° C. and 189° C. due tomelting/decomposition.

DSC of the citrate solid residue (see FIG. 36) showed three endothermicevents with peak temperatures at 134.3° C. (6.1 J/g heat of fusion),212.6° C. (23.1 J/g heat of fusion), and 221.5° C. (9.61 J/g heat offusion), respectively. TGA of the citrate solid residue showed atwo-step weight loss of 0.5% between room temperature and 120° C. due topossible dehydration/desolvation, and 21.9% between 120° C. and 194° C.due to melting/decomposition.

DSC of the malate solid residue (see FIG. 37) showed one endothermicevent due to melting with a peak temperature at 195° C. (108.3 J/g heatof fusion). TGA of the malate solid residue showed a two-step weightloss of 0.9% between room temperature and 146° C. due to possibledehydration/desolvation, and 16.3% between 146° C. and 237° C. due tomelting/decomposition.

Example 6: Moisture Sorption Analysis

The moisture sorption analysis was performed using a Hiden Isochemasystem Model IGAsorp. The sample was run in a stainless-steel meshcrucible. The sample was initially dried at 60° C. for 30 minutes thenthe moisture profile was evaluated by monitoring vaporadsorption/desorption over the range of 0 to 90% relative humidity at25° C. The moisture profile consisted of 2 cycles of vaporadsorption/desorption.

Dynamic vapor sorption was performed on Compound A (prepared asdescribed in example 1 above), the HCl salt of Compound A, phosphatesalt of Compound A, and mesylate salt of Compound A and the moisturesorption spectra obtained (see, FIGS. 7, 9, 38, and 40, respectively).Following DVS, the samples of Compound A, phosphate salt of Compound Aand mesylate salt of Compound A were subjected to XRPD (see, FIGS. 8,39, and 41, respectively).

DVS of the phosphate salt (see FIG. 38) showed that it was hygroscopicwith moisture adsorption of 13% up to 90% relative humidity. Nohysteresis was observed and it retained 0.6% moisture at the end of thesecond cycle. XRPD of the solid residues remaining after DVS showed nochange in the crystalline form.

DVS of the mesylate salt showed that it was hygroscopic with moistureadsorption of 0.2% up to 60% relative humidity and a total of 17% up to90% relative humidity. Very little hysteresis was observed and itretained 0.2% moisture at the end of the second cycle while there is astrong hysteresis between 80%-60% relative humidity during thedesorption cycle. XRPD analysis of the solid residue remaining after DVSof the mesylate salt was unchanged relative to the XRPD of a sample ofthe mesylate salt measured before DVS (see FIG. 41, where the top/upperspectrum represents the XRPD of a sample of the mesylate salt beforeDVS, and the bottom/lower spectrum represents the XRPD of a sample ofthe mesylate salt after DVS).

The disclosures of each patent, patent application, and publicationcited or described in this document are hereby incorporated herein byreference, in its entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

What is claimed is:
 1. A pharmaceutically acceptable salt form of4-cyano-N-[2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl]-1H-imidazole-2-carboxamide(Compound A)

wherein the pharmaceutically acceptable salt is selected from the groupconsisting of Compound A, sulfate salt; Compound A, phosphate salt;Compound A, mesylate salt; Compound A, tosylate salt; and Compound A,besylate salt.
 2. The salt form of claim 1 that is Compound A, sulfatesalt.
 3. The salt form of claim 2, in an amorphous form.
 4. The saltform of claim 2, characterized by a differential scanning calorimetrythermogram comprising endothermic events with peak temperatures at about47.4° C., about 207.2° C., and about 232.8° C.
 5. The salt form of claim1 that is Compound A, besylate salt.
 6. The salt form of claim 5, in acrystalline form.
 7. The salt form of claim 5, characterized by an X-raypowder diffraction pattern comprising peaks at 5.8, 6.3, 17.1, 17.4, and17.6 degrees two theta±0.2 degrees two theta.
 8. The salt form of claim7, wherein the X-ray powder diffraction pattern further comprises one ormore of the following peaks: 7.8, 8.6, 8.9, 18.2, 18.9, 19.6 or 23.0degrees two theta±0.2 degrees two theta.
 9. The salt form of claim 5,further characterized by an X-ray powder diffraction patternsubstantially as depicted in FIG.
 24. 10. The salt form of claim 5,characterized by a differential scanning calorimetry thermogramcomprising endothermic events with peak temperatures at about 51.5° C.,about 164.8° C., and about 212.2° C.
 11. A pharmaceutical compositioncomprising the salt form of claim 1 and at least one pharmaceuticallyacceptable excipient.
 12. A method of inhibiting colony-stimulatingfactor-1 receptor in a subject, said method comprising administering tosaid subject at least one salt form of claim 1 to said subject.
 13. Amethod of treating a disease that is at least one of osteoporosis,Paget's disease, rheumatoid arthritis and other forms of inflammatoryarthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma,myeloma, or tumor metastasis to bone in a subject comprisingadministering a therapeutically effective amount of at least one saltform of claim 1 to said subject.
 14. The method of claim 19, whereinsaid disease is rheumatoid arthritis or cancer.
 15. The method of claim19, wherein said disease is cancer metastasis to bone.
 16. A method oftreating a disease that is at least one of glomerulonephritis,inflammatory bowel disease, sarcoidosis, congestive obstructivepulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis,HIV infection, psoriasis, diabetes, tumor-related angiogenesis,age-related macular degeneration, diabetic retinopathy, restenosis,schizophrenia, or Alzheimer's dementia in a subject comprisingadministering a therapeutically effective amount of at least one saltform of claim 1 to the subject.
 17. A method of treating pain in asubject comprising administering to the subject a therapeuticallyeffective amount of at least one salt form of claim 1 to the subject.18. A method of treating a disease that is at least one of ovariancancer, uterine cancer, breast cancer, prostate cancer, lung cancer,colon cancer, stomach cancer, or hairy cell leukemia in a subjectcomprising administering a therapeutically effective amount of at leastone salt form of claim 1 to the subject.
 19. A method of treating orpreventing metastasis from ovarian cancer, uterine cancer, breastcancer, prostate cancer, lung cancer, colon cancer, stomach cancer, orhairy cell leukemia in a subject comprising administering atherapeutically effective amount of at least one salt form of claim 1 tothe subject.
 20. A method of treating an autoimmune disease that is atleast one of systemic lupus erythematosus, rheumatoid arthritis andother forms of inflammatory arthritis, psoriasis, Sjogren's syndrome,multiple sclerosis, or uveitis in a subject comprising administering atherapeutically effective amount of at least one salt form of claim 1 tothe subject.
 21. The method of claim 23, wherein the pain is selectedfrom skeletal pain caused by tumor metastasis or osteoarthritis, orvisceral, inflammatory, or neurogenic pain.